Molecular in vivo imaging with the high-resolution and sensitive positron emission tomography (PET) technique requires the preparation of a positron-emitting radiolabeled probe or radiotracer. For this purpose, fluorine-18 is becoming increasingly the radionuclide of choice due to its adequate physical and nuclear characteristics, and also because of the successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), which is currently the most widely used PET-radiopharmaceutical and probably the driving force behind the growing availability and interest for this positron-emitter in radiopharmaceutical chemistry. With a few exceptions, radiofluorinations involving fluorine-18 of high specific radioactivity (e.g. > 185 GBq/micromole) had, until recently, been limited to nucleophilic substitutions in homoaromatic and aliphatic series with [18F]fluoride. Considering chemical structures showing a fluoropyridinyl moiety, nucleophilic heteroaromatic substitution at the ortho-position with no-carrier-added [l8F]fluoride, as its K[18F]F-K222 complex, appears today as a highly efficient method for the radiosynthesis of radiotracers and radiopharmaceuticals. This chapter summarizes the recent applications of this methodology and highlights its potential in the design and preparation of, often drug-based, fluorine-18-labeled probes of high specific radioactivity for PET imaging, including macromolecules of biological interest such as peptides, proteins and oligonucleotides.